title: Histone deacetylase inhibitor LAQ824 augments inflammatory responses in macrophages through transcriptional regulation of IL-10.
abstract: APCs are important in the initiation of productive Ag-specific T cell responses and the induction of T cell anergy. The inflammatory status of the APC at the time of encounter with Ag-specific T cells plays a central role in determining such divergent T cell outcomes. A better understanding of the regulation of proinflammatory and anti-inflammatory genes in its natural setting, the chromatin substrate, might provide novel insights to overcome anergic mechanisms mediated by APCs. In this study, we show for the first time, to our knowledge, that treatment of BALB/c murine macrophages with the histone deacetylase inhibitor LAQ824 induces chromatin changes at the level of the IL-10 gene promoter that lead to enhanced recruitment of the transcriptional repressors HDAC11 and PU.1. Such an effect is associated with diminished IL-10 production and induction of inflammatory cells able of priming naive Ag-specific T cells, but more importantly, capable of restoring the responsiveness of anergized Ag-specific CD4(+) T cells.
authors.affiliation: Department of Immunology and Malignant Hematology, H. Lee Moffitt Cancer Center, Tampa, FL 33613, USA.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Wang
authors.forename: Fengdong
authors.initials: F
authors.lastname: Cheng
authors.forename: Karrune
authors.initials: K
authors.lastname: Woan
authors.forename: Eva
authors.initials: E
authors.lastname: Sahakian
authors.forename: Oscar
authors.initials: O
authors.lastname: Merino
authors.forename: Jennifer
authors.initials: J
authors.lastname: Rock-Klotz
authors.forename: Ildefonso
authors.initials: I
authors.lastname: Vicente-Suarez
authors.forename: Javier
authors.initials: J
authors.lastname: Pinilla-Ibarz
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Wright
authors.forename: Edward
authors.initials: E
authors.lastname: Seto
authors.forename: Kapil
authors.initials: K
authors.lastname: Bhalla
authors.forename: Alejandro
authors.initials: A
authors.lastname: Villagra
authors.forename: Eduardo M
authors.initials: EM
authors.lastname: Sotomayor
mesh_terms: D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D006877:Hydroxamic Acids / Q000494:pharmacology*; D007211:Indoles; D018836:Inflammation Mediators / Q000494:pharmacology*; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics* / Q000378:metabolism; D017737:Macrophages, Peritoneal / Q000187:drug effects / Q000201:enzymology / Q000276:immunology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D000077767:Panobinostat; D013154:Spleen / Q000166:cytology / Q000201:enzymology / Q000276:immunology; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology*
chemical_list: D000276:Adjuvants, Immunologic; D056572:Histone Deacetylase Inhibitors; D006877:Hydroxamic Acids; C556062:IL10 protein, mouse; D007211:Indoles; D018836:Inflammation Mediators; C477361:LAQ824; D016753:Interleukin-10; D000077767:Panobinostat